Procedure for preparation of progesterone



' pure pregnenolone.

Patented Jam 6 1948 znaaue; v PROCEDURE FOR PREPARATION OF 1raoaas'ranonn Percy L. JulianpMaywood, John Wayne Cole,

Chicago, vArthur Magnani,

Wilmette, and

.- Harold E. Conde, Chicago, 111., aaslgnors to The leveland, Ohio, atcorpora- Game; Company,

tibn ofOhio no Drawing.-

'I 'he present invention relates to the degradationotbile acids andsimilar acids-obtained by the oxidation degradation of steroids, andmore particularly relates to an improvement in the Barbier wielandprocessfor converting bisnorcholenic' acid to progesterone. v

With his discovery of 3-hydroxy bisnorcholenic acid from'the plantsterol, Stigmasterol, Ann. 507 128 (1933), Fernholz immediately realizedthat a Barbier-Wieland' degradation ,off this acid, Gilman; OrganicChem., vol. II, page'1357 (1943),

followed by oxidation of the -3-hydroxy group, would leadtoprogesterone, 'Ber. 67 1855, 2027 (1934). AlmostsimultaneouslyButenandt,whose brilliant work on the isolation of thecorpus luteum hormone from natural'sources had corroborated-theearlierwork of Allen and his coworkers,.likewise saw the significance ofFernholzs discovery, Ber; 6'] 1611, 1901, 2085 (1934). Both of'thes'eworkers almost simultaneously applied the 'Barbier-Wielandtechnique toFernholzs acid, Butenandt apparently finishing andpublishinghis-experiments. a short time before those oi Fernhola cameinto print. I

Neither 10f these; workers, however, departed essentially. from thetraditional Barbier-Wieland procedure nor'jdid they improve upon thisprocedure in the case'of the substances they were working with. Thus atotal of at least-seven distinct steps wasinvolve'd in going from3-acetoxy bisnorcholenicacid to progesterone. These steps may beoutlined as follows:

Step -1.Conversion of the acid ester '(viadiazo-methane). Q

Step 2.'-'Conversion of the methyl ester to3-hydroxy'ternorcholenylediphenyl carbinol.

into its methyl Step. 3.-' Acetylation of the 'ternorcholenyl-di Iphenyl-carbinol and dehydration to the corresponding' diph'enylethylene. r

Step 4.'Ozon izatlon of the diphenyl-ethylene to pregnenol'one acetate.Y

Application February '10. 1944, Serial No. 521,851

serum. (or. zoo-c973) z tion to provide an improved process forproducing progesterone.

A further object is to provide a simplified process oi preparingprogesterone from bisnorcholenic acid.

An additional object is to reduce greatly the number of steps involvedin producing progesterone irom bisnorcholenic acid. I

Another object is to provide a new process for decomposing ozonides ofthe type where R and R are hydrocarbon residues, and R is a cyclopentanohydrophenanthrene nucleus,

to the corresponding ketones;

A..further object is to provide a new process for converting carbinolsof the type Step 5 .'--.Conversion of pregnenolone acetate into itssemiecarbazone for isolation and purification. n Y, I. J I

Step'6'. Hydrolysis of, the semi-carbazone to Sept. "7..0ikidation ofthe 3'-hydroxy group of bility of Stigmasterol, made a commercialexploitationof the Fernholz-Butenandt procedure for the preparation ofprogesterone impractical.

It'is'accordingly an object of the present inven-' Other objects will beapparent to those skilled in the art from the following description. InUnited States Patents Nos. 2,218,971, 2,273,045 and 2,273,046 there aredisclosed pro- .cedures which make Stigmasterol readily accessible. InUnited States Patent No. 2,304,100 there Barbier-Wieland procedureoutlined above was eliminated, whereby the acid can be converteddirectly into the-carbinol of Step 2 without going through thecommercially difficult step of esterification with explosivediazo-methane.

1 In the present invention further improvements in the procedure leadingto the preparation of progesterone are obtained, and the processinvolves the complete elimination of Step 3 above,

- and the replacement of the remaining four steps by one operativeprocedure.

Thus the seven steps of the above procedure now become a twostepoperation of great simplicity which yields a hormone or a high degree ofpurity and in greatly enhanced yields. v

' Briefly outlined a preferred mode of carrying out the processcomprises treating the carbinol in glacial acetic acid with halogen,passing in ozone, adding an oxidizing agent such as chromic acid, then adehalogenating agent-all carried out in one operation. In short thecarbinol is dissolved in glacial acetic acid and, after addition of thereagents indicated above, and progesterone is isolated from thesolution.

To efiect this very simplified and time-saving procedure, certain novelchemical reactions had v to be introduced. Thus vigorous ozonization oithe free carbinol gave better yields of an ozonide than those obtainedby ozonization of the diphenyl-ethylene such as is described in Step 4above. To our knowledge this is the first time that a carbinol has beenso directly converted into the ozonide of its corresponding ethylene andthe invention comprises, interalia, this method ;of treating tertiarycarbinols of the type herein contemplated.

After addition of sufllcient chromic-acid to the ozonide to convert theB-hydroxy group into the 3-keto group, a solution of chromous chlorideis added. Instead of chromous chloride we have also been able to usequite successfully vanadous chloride or a 20% commercial solution oftitanous chloride. Our yields are greatly enhanced by the smooth actionof such highly reducing agents as chromous chloride in effecting cleancleavage of the ozonide as well as complete and smooth dehalogenation.This novel method of dehalogenating has in this case as well as inothers proved to be a most useful tool and may be used-for treatingcompounds of the general type contemplated herein.

Following the treatment of an acetic acid solution of 3-hydroxyternor-cholenyl-carbinol by bromine, ozone, chromic acid, and chromouschloride, all in direct succession in the same reaction vessel, it isvery easy to separate from the solution progesterone of a high degree ofpurity.

The following examples serve to illustrate the invention:

Example I (recrystallized from chloroform) in 250 cc. gla-' cial aceticacid is added at a room temperature 4 tion is concentrated under thevacuum of a wate pump and at 80 to 90 C. until 500 to 600 cc.-ofdistillate have collected.

The reaction mixture is now diluted with 3 to 4 volumes of water andextracted four times with ether. The ether extractions are washedsuccessively with water, 10% sodium hydroxide solution, and water again.The washed ether extracts are combined, concentrated and steamdistilled. The residue from the steam distillation is cooled, taken upin ether and the ether extract again washed successively with. water,dilute a solution of 2.7 cc. (8.4) grams of bromine in 150 cc. ofglacial acetic acid. The solution is warmed to 96100 F. and anozone-oxygen mixture containing 3 to 4% of ozone by volume passed in for30 minutes at a rate of flow of 3.5 liters per minute. The dibromide ofthe carbinol usually crystallizes out ,of solution toward the end of thebromination time and the solution should be clear at the end of theozonization. During the ozonization the temperature rises severaldegrees.

The solution after ozonization is cooled at once to 70 F. and theoxidizing mixture, cooled before using, and consisting of 10 gramschromic oxide, 1 cc. concentrated sulfuric acid, 15 cc. of water and 80cc. glacial acetic acid, is added with stirring during several minutes,never allowing the temperature of the reaction mixture to rise above 80F. After standing for 1 hour at room temperature, 20 cc. of methanol isadded to the reaction mixture. The reaction mixture is now diluted with500 cc. of glacial acetic acid and the resulting solution cooled to 60F. 300 cc. of one molar chromous chloride solution, prepared accordingto the procedure of Conant and Cutter, J. A. C. S-., 48 1023 (1926), isthen added with shaking under an atmosphere of carbon dioxide. Afterstanding for /2 hour (or the solution may stand as long as over night,if desired), the solusodium hydroxide and water.

Example II The procedure was identical with that in Ex-' ample I exceptthat the chromous chloride was replaced by 300 cc. of a 1 molar solutionof vanadous chloride prepared according to the method of Conant andCutter, J. A. C. S., 48 1023 (1926), and the vanadous chloride was addedto the mixture without dilution of the mixture prior to the addition ofthe debrominating agent. The crude progesterone had a melting point of117 to 124 C.

Example III The procedure was the same as in Example I except that 300cc. of a commercial 20% solution of titanous chloride was used as thedebrominating agent. and there was no dilution of the reaction mixtureprior to the addition of thedebrominating agent. The crude progesteronehad a melting point of 117 to 124 C.

Example IV The procedure was the same as in Example III, except that thereaction mixture was heated on a steam cone for one hour for thedebromination. The crude progesterone had a melting point of 113 to 119C.

Other oxidizing agents than chromic acid which are capable of convertingthe 3-.OI-I group to a keto group may be employed, such as chromates andpermanganates. In certain phases of the invention the nuclear doublebond may also be protected by the use of other known removable reagentssuch as hydrobromides, etc.

The method for decomposing ozonides and dehalogenation by the use of thechromous. vanadous and titanous salts, which method is a significantfeature of this invention, is also applicable where the 3-OH group isnot oxidized to the 3-ket'o group. Thus the series of steps outlinedabove for the preparation of progesterone may be altered in that afterbromination and ozonization the resulting ozonide is treated directlywith the chromous, vanadous or titanous salts toyield pregene5-3-ol-2Q-one. Obviously this procedure is applicable. where thestarting material contains a 3-acyloxy group. H

The process of the present invention may be The final ether I solutionis concentrated to a volume of about 20 v employed with other carbinolsthan the diphenyl' carbinol. In general any carbinol of the formulacarbinols of the formula CH: /CII CHI IEC-C R R which upon dehydrationforms ethylenes of the type in which R is hydrogen or a hydrocarbonradical ma be used.

Reference is made to copending application Serial No. 521,850 filedconcurrently herewith, now Patent No. 2,374,683. I

Having described the invention what is claimed 1. The process whichcomprises the steps of first treating S-hydroxy A-ternorcholenyldiphenyl carbinol with bromine, ozonizing the brominated material,convertin the 3-hydroxy group of the ozonization product toa keto group,treating the resulting 3-keto compound with a dehalogenating agent, allwithout isolation of intermediates, and recovering progesterone from thereaction mixture.

2. The process or claim 1 in which the dehalo- 'genating agent ischromous chloride.

3. The process of claim 1 in which the dehalogenating agent is vanadouschloride.

4. The process 01 claim 1 in which the dehalogenating agent is titanouschloride.

5. The process of producing progesterone which comprises successivelytreating a solution 01' 3-hydroxy A-ter-norcholeny1 diphenyl carbinol inacetic acid with bromine, ozone, chromic acid, and chromous chloride,without isolation of intermediates, and recovering progesterone from thereaction mixture.

6. The method of converting ter-nor-cholenyl on. on c-c-n wherein Rrepresents phenyl radicals, and R is an etio-chlolenyl radical, intoketones of the formula which comprises subjecting said carbinols to theaction of first bromine and then ozone, and decomposing the ozonide witha reducing agent.

7. The process which comprises successively treating 3-hydroxy Aternorcholenyl diphenyl carbinol with bromine and then treating thebromination product with ozone.

8. The process of producing progesterone whichcomprises successivelytreating a solution of 3- hydroxy A ternorcholenyl diphenyl carbinolwith bromine, ozone, chromic acid, and a debrominating agent, withoutisolation of intermediates and recovering progesterone from the reactionmixture. Y

PERCY L. JULIAN. JOHN WAYNE COLE. ARTHUR MAGNANI. HAROLD E. CONDE.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,232,438 Butenandt Feb. 18, 19412,304,100 Julian Dec. 8, 1942

